Formulation of poorly water soluble active agents, particularly in liquid and semi-solid forms, is a challenging task due to incompatibility between the carrier and the fill material. This incompatibility can result in agglomerization of the active agent over time which can result in low in vitro/in vivo dissolution. Further, active agents which have low solubility in water and/or low absorption in vivo (classified as BCS Class II and Class IV active agents under the Biopharmaceutical Classification System) can be difficult to integrate into a formulation due to the uncertainty surrounding the correlation between in vitro and in vivo performance. For example, BCS Class II and Class IV active agents can exhibit significant food effects, particularly with high fat meals.
Different techniques for enhancing the solubility and bioavailability of water soluble active agents have been described in the literature. U.S. Pat. No. 5,145,684 to Liversidge et al. describes dispersible particles containing a crystalline active agent substance having a surface modifier absorbed on the surface thereof. The particles are made by wet milling in the presence of grinding media in conjunction with a surface modifier. Liversidge does not disclose or suggest making microparticles by melting or dissolving a water-insoluble active agent in a coating material and adding the mixture to a hydrophilic or lipophilic carrier to form microparticles.
U.S. Pat. No. 6,652,881 to Stamm et al. describes compositions containing micronized fenofibrate, wherein the compositions have a dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes, and 75% in 30 minutes as measured using the rotating blade at 75 rpm according to the European Pharmacopoeia, in a dissolution medium constituted by water with 2% by weight polysorbate 80 or 0.025 M sodium lauryl sulfate. The compositions contain an inert hydrosoluble carrier covered with at least one layer containing a fenofibrate active ingredient in a micronized form, a hydrophilic polymer, and optionally a surfactant; and optionally one or several outer phase(s) or layer(s). Stamm does not disclose or suggest making microparticles by melting or dissolving a water-insoluble active agent in a coating material and adding the mixture to a hydrophilic or lipophilic carrier to form microparticles.
U.S. Pat. No. 6,375,986 to Ryde et al. describes solid dose nanoparticulate compositions comprising a poorly soluble active agent, at least one polymeric surface stabilizer, and dioctyl sodium sulfosuccinate (DOSS). The polymeric surface stabilizer is adsorbed on the surface of the active agent in an amount sufficient to maintain an effective average particle size of less than about 1 micron. Ryde does not disclose or suggest making microparticles by melting or dissolving a water-insoluble active agent in a coating material and adding the mixture to a hydrophilic or lipophilic carrier to form microparticles.
U.S. Pat. No. 5,545,628 to Deboeck et al. describes a pharmaceutical composition for treating hyperlipidemia or hypercholesterolemia or both in a mammal, which contains an effective amount of each of fenofibrate and an excipient containing one or more polyglycolyzed glycerides. The compositions are prepared by co-melting the fenofibrate and the polyglycolyzed glycerides to form a homogeneous mixture or solution. The molten mixture can be filled into hard gelatin capsules. Deboeck does not disclose or suggest making microparticles by melting or dissolving a water-insoluble active agent in a coating material and adding the mixture to a hydrophilic or lipophilic carrier to form microparticles.
WO 2006/062933 to Reliant Pharmaceuticals, Inc. describes fenofibrate compositions containing fenofibrate solubilized in fatty acid esters. The acid portion or the ester portion of the fatty acid is a C1-C15 group, preferably a C1-C6, more preferably a C1-C4 group. The fenofibrate may be dissolved in the fatty acid esters with or without the use of heat, preferably without heating. The '933 application does not disclose or suggest making microparticles by melting or dissolving a water-insoluble active agent in a coating material and adding the mixture to a hydrophilic or lipophilic carrier to form microparticles.
There exists a need for additional methods for enhancing the solubility and bioavailability of water-insoluble active agents.
Therefore, it is an object of the invention to provide methods for enhancing the solubility and bioavailability of water-insoluble active agents.
It is further an object of the invention to provide compositions which exhibit enhanced solubility and bioavailability of water-insoluble active agents and methods of using thereof.